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NM_001267550.2(TTN):c.38737G>T (p.Glu12913Ter) AND TTN-related condition

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 2, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003918233.1

Allele description [Variation Report for NM_001267550.2(TTN):c.38737G>T (p.Glu12913Ter)]

NM_001267550.2(TTN):c.38737G>T (p.Glu12913Ter)

Gene:
TTN:titin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.2
Genomic location:
Preferred name:
NM_001267550.2(TTN):c.38737G>T (p.Glu12913Ter)
HGVS:
  • NC_000002.12:g.178653292C>A
  • NG_011618.3:g.182511G>T
  • NM_001256850.1:c.34523-751G>T
  • NM_001267550.2:c.38737G>TMANE SELECT
  • NM_003319.4:c.13283-10975G>T
  • NM_133378.4:c.31742-751G>T
  • NM_133432.3:c.13658-10975G>T
  • NM_133437.4:c.13859-10975G>T
  • NP_001254479.2:p.Glu12913Ter
  • LRG_391t1:c.38737G>T
  • LRG_391:g.182511G>T
  • NC_000002.11:g.179518019C>A
  • NM_001267550.1:c.38737G>T
Protein change:
E12913*
Links:
dbSNP: rs767120669
NCBI 1000 Genomes Browser:
rs767120669
Molecular consequence:
  • NM_001256850.1:c.34523-751G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_003319.4:c.13283-10975G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133378.4:c.31742-751G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133432.3:c.13658-10975G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_133437.4:c.13859-10975G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001267550.2:c.38737G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
TTN-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004730004PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Dec 2, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004730004.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The TTN c.38737G>T variant is predicted to result in premature protein termination (p.Glu12913*). This variant has been reported in the heterozygous state in an individual with congenital hypertonia and cardiomyopathy and a second TTN variant was not identified (Supplemental Table, Gonzalez-Quereda L et al. 2020. PubMed ID: 32403337). RNAseq studies from heart tissue indicate this exon is not commonly included in TTN mRNA transcripts (PSI of 3%-5%; Roberts A.M. et al. 2015. PMID: 25589632;https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is less likely to cause autosomal dominant TTN-related disorders (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). This variant is found in an exon specific to the TTN metatranscript and is not included in the skeletal muscle isoform (NM_133378.4); however, many other protein truncating variants in metatranscript-only exons have been recently observed in severe recessive congenital titinopathies (Bryen et al. 2020. PubMed ID: 31660661; Oates et al. 2018. PubMed ID: 29691892; Chervinsky et al. 2018. PubMed ID: 29575618). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Taken together, we classify the c.38737G>T (p.Glu12913*) variant as likely pathogenic for autosomal recessive titinopathies and as uncertain for autosomal dominant TTN-related disorders.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 16, 2024